Alzheimer's disease: ageing-related or age-related? New hypotheses from an old debate

The view that Alzheimer's disease (AD) is a fatal outcome of ageing prevails over the view that it mainly affects people aged 75-95. The former is based on the exponential increase in the incidence of AD with ageing, while the latter on AD prevalence rates. Both views share the idea that neurofibrillary degeneration (NFD) is secondary to the loading of β-protein (Aβ) and its more toxic species in nervous tissue that occurs with ageing in everybody, but is greater in people predisposed to AD. They differ in terms of the complexity attributed to the concept of neuronal vulnerability to Aβ. In the ageing-related hypothesis, it is seen as a phylogenetic characteristic of neurons that predisposes some of them to Aβ-dependent NFD, which spreads from the more vulnerable allocortex to the less vulnerable neocortex and accordingly causes memory decline progressing to dementia. To adapt this to the discontinuity of AD prevalence, it is necessary to see neuronal vulnerability as being modulated by additional ontogenetic factors that make some vulnerable neurons more or less sensitive to Aβ toxicity. This may give the Aβ/NFD relationship enough flexibility to explain the cognitive reserve of the oldest old and the phenotypical variability of AD, in particular why it is that the clinical onset of AD may be characterised by focal signs other than memory loss. Introducing this concept offers a new perspective of AD pathogenesis based on the role played by Aβ and related proteins in nerve cell selection during brain development and adult neurogenesis.